This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective of this project is to elucidate mechanisms of infection-induced preterm labor in order to develop rational interventional strategies to prevent preterm birth and neonatal sequelae of prematurity (i.e. brain injury). Intra-amniotic infection causes the majority of early preterm births. Immune responses to bacteria are thought to drive infection-induced preterm labor and no effective therapy to prevent preterm birth currently exists. If interventions to prevent preterm birth and fetal injury are to become realistic goals, then the pathways that are activated in the cervix, uterus, placenta and fetus in response to infection and inflammation need to be elucidated in a model which emulates human disease. The proposed study will establish a new model of preterm birth in a chronically catheterized nonhuman primate (NHP) using E. coli and lipopolysaccharide (LPS) to induce an intra-amniotic infection. Our main hypothesis is that inflammation resulting from toll-like receptor 4 (TLR4) signaling is a critical mediator in the pathogenesis of preterm labor, by initiating an inflammatory response. TLR4 recognizes LPS, a gram-negative bacterial product. A hierarchy of TLR4 signaling can be established by using bacterial mutants with LPS structural variants to dissect maternal inflammatory responses that may aid bacteria in trafficking across the fetal membranes into the amniotic fluid.